The hypothalamus is a small, central part of the brain with several important regulatory functions, for example as regards physiologic response to external stress, body weight (especially the metabolically unfavorable abdominal obesity), the sleep-wake cycle and mood fluctuations. As shown in FIG. 1, the hypothalamus 2 is connected to the pituitary 3 as part of the central nervous system 1 and controls the secretion of different hormones from this endocrine gland. One of these hormones is ACTH (adenocorticotropic hormone), the secretion of which is activated through secretion of corticotropin releasing hormone (CRH) from the hypothalamus 2, as indicated by reference numeral 7 in FIG. 1. In response, this will activate secretion of the stress-related hormone cortisol 6 from the cortex of the adrenal glands 5 (see reference numerals 8 and 9 in FIG. 1).
Cortisol 6 circulates in the bloodstream and activates specific receptors, such as the glucocorticoid receptor (GR), in another small part of the brain, the hippocampus 4. This activation is indicated as 10 in FIG. 1 and leads to inhibition of the release of ACTH (reference numeral 11) as well as CRH (reference numeral 12). Thus a feedback loop is established, which regulates the blood concentration of cortisol.
The joint operation of the above functions, in the medical literature commonly referred to as the hypothalamic-pituitary-adrenal (HPA) axis, constitutes an important mechanism for maintaining steady state in the human organism. Disturbances in this mechanism have been shown to lead to metabolic complications, such as increased insulin resistance and abdominal obesity. These metabolic abnormalities are associated with increased risk for cardiovascular disease, the major cause of death in industrialized countries. A review of the above is found in “Neuroendocrine perturbations as a cause of insulin resistance” in Diabetes/Metabolism Research and Reviews 1999; 15:427–441, by Björntorp P. For a more detailed description see “Psychoneuroendocrine aspects on the metabolic syndrome”, ISBN 91-628-3195-X, by Rosmond R., Göteborg University 1998.
Abnormal concentrations of cortisol have also been shown to be the biochemical mechanism for the influence of external stress factors on the metabolic system, which lead to increased risk for heart disease, in both humans and experimental animals.
Since the concentration of this hormone in blood serum shows diurnal variation, the functional analysis of the HPA axis requires a number of cortisol measurements during the day, usually seven to ten, and may also have to be complemented by further examinations.
The saliva level of cortisol is strongly correlated to the level in blood serum, as reported by Aardal E. and Holm AC. in “Cortisol in saliva—reference ranges and relation to cortisol in serum” in European Journal of Clinical Chemistry and Biochemistry 1995:33(12):927–32. Test equipment for measuring the amount of saliva cortisol, using Radio Immune Assays (RIA), are commercially available from Orion Diagnostica, Espoo, Finland and have been used to characterize the HPA axis in a population based study. However, the identification of abnormalities has up to now only been possible by means of statistical analysis of groups of subjects. Due to the large inter- and intra-individual variability, it has hitherto not been possible to classify individual subjects.
Testosterone is the male sexual hormone but is present also in females, albeit in a very low concentration. This hormone interacts with cortisol in a fairly complex way, as described by Björntorp P. in “Hypothalamic origin of prevalent human disease” in “Hormones, Brain and Behaviour”, Academic Press, 2001 (in press), which can be summarized as follows:
1. In males low testosterone implies a more negative response to cortisol alteration, compared to the average or intermediate testosterone level. However, a high testosterone level also implies negative effects. Therefore, three levels of testosterone have to be defined, i.e. low, normal/intermediate and high. In males the gonads, i.e. the testicles, secrete most of the testosterone.
2. In females testosterone levels are normally low, i.e. testosterone may be close to zero without identifiable negative effects. However, testosterone levels in the upper quartile in a normal population are associated with increased risk for cardiovascular disease, and this relationship is stronger when cortisol levels are abnormal. It is assumed that the testosterone in females is secreted by the adrenal cortex, as is cortisol.
In a recent study by Shifren J L, Braunstein G D, Simon J A, et al., “Transdermal testosterone treatment in women with impaired sexual function after oophorectomy”, N Engl J Med (United States), September 2000, 343(10) p 682–8, it was found that a certain (very low) level of testosterone may be necessary also for women, in order to maintain general well-being and a satisfying sex life.
Testosterone can be measured in saliva, using the same principle as when measuring cortisol, as reported by Obminski Z and Stupnicki R in “Comparison of the testosterone-to-cortisol ratio values obtained from hormonal assays in saliva and serum” in J Sports Med Phys Fitness 1997 March; 37(1):50–55, by Navarro M A et al. In “Salivary testosterone in postmenopausal women with rheumatoid arthritis”, J Rheumatol 1998 June; 25(6):1059–62 and by Granger D A et al in “Salivary testosterone determination in studies of child health and development” in Horm Behav 1999 February; 35(1):18–27.